The proanthocyanidins have attracted a great deal of attention in the fields of medicine and nutrition due to the wide range of their biological activities (e.g. U.S. Pat. No. 6,638,971). Applicants have now discovered specific anti-cancer properties of procyanidins and derivatives thereof and their effect on regulation of proteins involved in the regulation of the cell cycle. Examples of such proteins are Cdc2, AKT, forkhead transcription factor, p53 and pRb.
Cdc2 is a protein kinase which is important in the control of both cell cycle and apoptosis [Konishi, Y. et al., Molec. Cell, 9: 1005-1016, 2002]. Phosphorylation of Cdc2 Tyr15 residue is inhibitory to its function and causes resistance to paclitaxel (Taxol®)-induced apoptosis [Tan, M. et al., Molec. Cell, 9: 993-1004, 2002].
AKT, encoded by a known oncogene, also known as protein kinase B, is a serine/threonine kinase that plays a central role in promoting the survival of a wide range of cell types [Khwaja, A., Nature, pp. 33-34 (1990)]. Inhibition of AKT induces apoptosis of human ovarian cancer cells which demonstrates that AKT may be an important target for cancer treatment and other proliferative disorders [Zang, Q. Y., et al, Oncogene, 19 (2000)]. In fact, AKT is commonly used as a marker for ovarian and breast cancers. AKT promotes cell survival by phosphorylating forkhead transcription factor (FKHR) at amino acid position Ser256, which results in inhibition of FKHR function [Brunet, A., et al., Cell, 96:857-868 (1999)]. AKT-mediated phosphorylation of Ser256 of FKHR inhibits apoptosis through decreasing FKHR-controlled Fas ligand expression [Jackson, J. G. et al., Oncogene, 198: 4574-4581, 2000; Nakamura, N. et al., Mol. Cell. Biol., 20: 8969-8982, 2000; Rena, G. et al., EMBO J., 21: 2263-2271, 2002.]
Early genetic changes associated with malignancy involve genes that regulate cell cycle progression and often these changes result in a loss of G1 checkpoint in tumor cells, due to defects in retinoblastoma (pRb) and p53 cell cycle pathways [Lomazzi, M. et al., Nat Genet., 31:190-194, 2002]. Post-transcriptional modification of these proteins appears to be an important mechanism of their functional regulation.
For example, phosphorylation of Ser392 of p53 activates specific DNA binding functions by stabilizing p53 tetramer formation [Keller, D. M. et al., Molec. Cell, 7: 283-292, 2001; Fiscella, M., et al., Oncogene, 9:3249-3257, 1994]. Several stress stimuli are reported also to phosphorylate Ser392 (Ser389 in mouse). In addition, recent analysis of p53 phosphorylation in human tumors revealed that among 10 sites analyzed, hyperphosphorylation of residues Ser15, Ser 81, and Ser392 and acetylation were among the most frequent modifications [Minamoto, T. K., et al., Oncogene, 20: 3341-3347, 2001]. Increased phosphorylation of p53 at Ser392 in human tumors is frequent [Furihata, M. et al., J. Pathol., 197: 82-88, 2002].
The serine residues of pRb are also critically involved in G1/S transition. It is known that cyclin D-Cdk4 phosphorylates pRb at Ser780 and possibly Ser795 [Kitagawa, M., at al., EMBO J., 15: 7060-7069, 1996; Panigone, S. et al., Oncogene, 19: 4035-4041, 2002]. Both transforming growth factor β (TGF-β) and retinoic acid have been reported to cause G1 cell cycle arrest by dephosphorylating pRb at Ser780, Ser795 and Ser807/811 [Hu, X. et al., Biochem. Biophys. Res. Commun., 276: 930-939, 2000; Dimbert, A. et al., Blood, 99: 2199-2206, 2002].
Thus, the cell cycle regulatory proteins are useful targets for tumor therapy. At present, there is a need in the art for compounds that can target hyperphosphorylation and/or overexpression of these proteins to prevent and/or treat proliferative growth. It has now been found that compounds of this invention and compositions thereof are effective for these uses.